3-methoxy-4-carbamidomethoxy-phenylacetic acid esters



United States Patent Office 3,086,978 Patented Apr. 23, 1963 3,tl86,978 S-METHOXY-d-CARBAMHDOMETHOXY- PHENYLACETIC Atlll) ESTERS Rudolf Hiltman, Hartmund Wollweher, Friedrich Hoffmeister, and Wolfgang Wirth, all of Wnppertal Elberfeld, Germany, assignors to Farbenfahriiren Bayer Aktiengeseilschaft, Leverirnsen, Germany, a corporation of Germany No Drawing. Filed May 5, 1961, Ser. No. 130,700

Claims priority, application Germany May 6, 1960 8 Claims. (Ci. 260-3263;)

4 3 -OCH:

dnioooR wherein R is an alkyl radical containing 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, butyl, or an alkenyl radical containing normally 3 to 4 carbon atoms, e.g. allyl, butenyl; and each of R and R is also an akyl radical containing 1 to 4 carbon atoms; or hydrogen, provided, however, that when one of the moieties represented by R and R" is hydrogen, the other is an alkyl radical. Alternatively, R and R" may be joined to provide a single alkylene radical containing from 4 to carbon atoms, and preferably 4 to 6 carbon atoms, the terminal carbons of which are thus attached to the single nitrogen atom to constitute a heterocyclic nitrogen-containing moiety, e.g. piperidino, pyrrolidino; or R and R may each be an alkylene radical connected at their terminal carbons positioned remote from the nitrogen atom through a hetero component, such as a chalcogen, for example, oxygen, to constitute a heterocyclic radical such as a morpholino group.

Illustrative of these compounds are 3-methoXy-4-N,N- diethylcarbamidomethoxy-phenylacetic acid ethyl ester, 3 methoxy 4 N tert. butylcarbamidomethoxyphenylacetic acid ethyl ester, 3-rnethoxy-4-pyrrolidinocarbamidomethoXy-phenylacetic acid ethyl ester, 3- methoxy 4-N,N-diethylcarbamidomethoxy-phenylacctic acid-n-propyl ester, 3-methoXy-4-N,N-diethylcarbamidomethoXy-phenylacetic acid methyl ester, and 3-rnethoxy- 4 N,N diethylcarbamidomethoxy phenylacetic acid-nbutyl ester.

The procedure for preparing the compounds of the invention are standard, and include, for example, the reaction of homovanillic acid alkyl or alkenyl esters with N-monoor N,N-dialkylated haloacetamides or with other reactive esters of N-alkylated glycollic acid amides in the presence of alkaline condensation agents. As starting substances, lower esters of homovanillic acid are preferably used, such as the methyl, ethyl, propyl, butyl, or allyl ester, with chloracetamides to the nitrogen atom of which is attached one or two 'alkyl radicals, each containing 1 to 4 carbon atoms, or a single alkylene radical, the terminal carbons of which are attached to the nitrogen atom to provide a heterocyclic amino moiety; or a ring structure wherein a plurality of carbon atoms are interrupted by, for example, a chalcogen atom to provide, by way of illustration, a morpholino group. Thus, the preferred and corresponding nitrogen substituents of the reactant chloracetamides are suitably characterized by the values R and R" of the general formula above defining the products of the invention. Illustrative of these amides are N-tert.-butyl-chloracetamide, N-propyl-ehloracetamide, N,N-diethyl-chloracetamide, chloracetyl-pyrrolidine, chloracetyl-piperidine and chloracetyl-morpholine. In order to prevent a transesterification, the alcohol corresponding to the ester is expediently used as a solvent. As a condensation agent, sodium alcoholate is especially suitable. However, hydroXyl group-free solvents such as toluene may likewise be used. In this case, the sodium compound of the ester used as a starting material is initially prepared by procedures well-known to those skilled in the art. A solvent which is particularly preferred for the conversion of these sodium phenolates is dimethylformamide in which sodium compounds are readily soluble.

Another method of preparation consists in esterifying appropriate N-alkyl-substituted 3 methoxy 4 carbamidomethoXy-phenylacetic acids with saturated or unsaturated aliphatic alcohols according to known methods. Lower N alkyl substituted 3-methoXy-4-carbamidomethoxy-phenylacetic acid alkyl esters such as the methyl ester may also be converted into the corresponding higher esters by transesterification with higher alcohols.

The N-alkyl-substituted 3-methoXy-4-carbamidomethoxy-phenylacetic acid alkyl and alkenyl esters encompassed by the general formula and obtained as described above are, as indicated, valuable agents for inducing narcosis. When administered to a subject intravenously, these compounds are capable of inducing a relatively brief narcotizing effect, as well as one of a depth and duration suilicient and efficacious for performance of surgery on the treated subject, while efiecting a rapid inception and withdrawal of the desired and operative degree of narcosis, thus providing a significantly more rapid return to street capacity in treated subjects than is available with narcotic agents employed for like purposes heretofore. This characteristic of the compounds of the invention is, of course, of decisive importance in instances of minor surgery where brief but relatively profound narcosis and, indeed, attainment of the complete tolerance stage, is required together with a rapid return to normal awareness and function on the part of the treated subject.

By way of illustrating the aforesaid advantages inherent in the esters described herein, 3-methoxy-4-N,N-dicthylcarbamidomethoxy-phenylacetic -acid-n-propyl ester, obtained by the practice of the invention, has been compared with the known narcotizing agent, S-methyl-S-cycloheXenyl-N-methyl-barbituric acid sodium salt. The results obtained by intravenousadministration to dogs is indicated in the following table:

3-methoxy-4-N, N-diethylcarbamidomethoxy-phenylacetie acid-m pronyl ester.

2 5-methyl-5-cyclohcxcnyl-N-rnethyhbarbituric acid.

1 Stage of narcosis VI corresponds, according to Magnus-Girndt, to deep narcosis with complete absence of reflexes; stage of nareosis IV corresponds to lateral position, the corneal and pinching reflexes being maintained. The period between the stages of narcosis VI and IV is an approximate measure of the time available for operation.

Similar results have been attained in tests undertaken with rabbits.

It has thus been determined that at equivalent dosages, the compounds of the invention effect the attainment in mammalian subjects of a like depth of narcosis to that achieved by compositions Widely known and employed heretofore, but differing from these latter compositions in the reduced total time of narcosis attained thereby; that is the period of time elapsed from the onset of the narcotized state to the disappearance of all narcotic symptoms, and hence a return to normal functioning of the subject, e.g. the street capacity of the individual.

The following examples are further illustrative of the invention.

Example 1 PREPARATION OF THE COMPOUND, 3-METHOXY-4- N,N-DIETHYLCARBAMIDOMETHOXY PHE NYLACETIC ACID ETHYL ESTER, OF THE FORMULA I ornoooonzn To 21 g. of homovanillic acid ethyl ester is added a solution of 2.3 g. of sodium in 100 ml. of alcohol. After driving off the alcohol under vacuum, the residue in the flask is dissolved in 100ml. of dimethylformamide. After the addition of 0.5 g. of sodium iodide, g. of chloracetic acid-N,N-diethylamide are added dropwise while stirring to the solution heated to 130 C., and the mixture is further heated, until the alkaline reaction has disappeared; a period of about three hours. From the cooled reaction mixture the precipitated salts are removed by filtering off with suction. After driving 00? the dimethylformamide under vacuum, the product is fractionated under vacuum, and 22.5 g. of '3-methoxy-4- N,N-diethylcarbamidomethoxy-phenylacetic acid ethyl ester of B.P. 204 C.207 C./0.6 mm. Hg is thus obtained as a water-insoluble yellowish oil.

Example 2 PREPARATION OF THE COMPOUND, 3-METHOXY-4-N- TERT. BUTYLCARBAMIDOMETHOXY-PHENYLACETIC ACID ETHYL ESTER, OF THE FORMULA a OCH;

( JHQC O O CaHs In the manner described in Example 1,' wherein an equivalent amount of chlor'acetic acid-N-tert. butyl amide is substituted for the amideemployed as a reactant therein, the product compound, 3-methoxy-4-N-tert.-butylcarbamidomethoxy-phenylacetic acid ethyl ester of B.P. 191 C. to 193 C./0.4 mm. Hg is produced.

Example 3 PREPARATION OF THE COMPOUND, 3-METHOXY-4- PYRROLIDINOCARBAMIDOMETHOXY PHENYLACETIC ACID ETHYL ESTER, OF THE FORMULA I oornoou -OCHa product compound, 3-methoxy-4-pyrrolidinocarbamidomethoxy-phenylacetic acid ethyl ester having a B.P. of 201 C.-204 C./1 mm. Hg is obtained.

Example 4 OOHzC ON To a solution of 4 g. of sodium in 200 ml. of n-propanol is added 39 g. of homovanillic acid-n-propyl ester (B.P. 160 C.-162 C./4 mm. Hg) and the mixture is concentrated by evaporation under vacuum. After dissolving the residue in 200 m1. of dimethylformamide and the addition of 0.5 g. of sodium iodide, 26.2 g. of chloracetic acid-N,N-diethylamide are added dropwise with stirring at an internal temperature of C., an the mixture is further heated at 130 C. for three hours. Working up of the reaction mixture according to Example 1 yields 44.3 g. of 3-methoxy-4-N,N-diethylcarbamidomethoxyphenylacetic acid-n-propyl ester as a yellowish oil of B.P. 210 C.-212 C./0.7 mm. Hg.

Example 5 PREPARATION OF THE COMPOUND, 3-METHOXY-4 N,N-DIETHYLCARBAMIDOMETHOXY PHENYLACETIC ACID METHYL ESTER, OF THE FORMULA OOHa (EH20 O 0 CH3 To a solution of 3.2 g. of sodium in 200 ml. of methanol are added 26 g. of homovanillic acid methyl ester (B.P. 149 C./ 6 mm. Hg), the mixture is concentrated by evaporation under vacuum and the residue dissolved in 200 ml. of dimethylformamide. After the addition of 0.5 g. of sodium iodide, 19.7 g. of chloracetic acid-N,N-diethylamide are added dropwise at 130 C. and the process is continued as described in Example 1. 18 g. of 3-methoxy 4 N,N-diethylcarbamidomethoxy-phenylacetic acid methyl ester of RP. 199 C.-2-0l C./0.6 mm. Hg are thus obtained as a pale yellow oil.

Example 6 PREPARATION OF THE COMPOUND, S-METHOXY-A- N,N-DIETHYLCARBAMIDOMETHOXY PHENYLACETIC ACID-n-PROPYL ESTER, OF THE FORMULA O OHZCON C2115 OOHa Fifty grams of the 3-methoxy-4-N,N-diethy1carbamidomethoxy-phenylacetic acid methyl ester prepared by the method described in Example 5 are dissolved in 300 ml. of n-propanol and, after the addition of 0.1 g. of sodiumn-propylate, heated in an effective column, until methanol no longer goes over. After driving on the excess propyl alcohol, the product'is distilled under vacuum and 46 g.

of the 3-methoxy-4-N,N-diethylcarbamidomethoxy-phenylacetic acid-n-propyl ester of RP. 210 C.212 C./0.7 mm. Hg described in Example 4 are thus obtained.

Example 7 PREPARATION OF THE COMPOUND, 3-METHOXY-4- N,N-DIETHYLCARBAMIDOMETHOXY PHENYLACETIC ACID ETHYL ESTER, OF THE FORMULA O CHzCON To a solution of 2.3 g. of sodium in 100 ml. of alcohol are added 21 g. of homovanillic acid ethyl ester and 0.5 g. of sodium iodide. The mixture is heated under a reflux condenser while stirring and g. of chloracetic acid-N, N-diethylamide are added dropwise. After boiling for a further eight hours, the alcohol is driven off under vacuum and the residue taken up with water and benzene. The separated benzene layer is washed with dilute sodium hydroxide solution and water and then dried over sodium sulphate. After driving olf the solvent, the product is dis- 25 tilled under vacuum and 21 g. of the 3-methoxy-4-N,N- diethylcarbamidomethoxy-phenylacetic acid ethyl ester of B.P. 204 C.207 C./().6 mm. Hg described in Example 1 are thus obtained.

Example 8 PREPARATION OF THE COMPOUND, 3-METHOXY-4- N,N-DIETHYLCARBAMIDOMETHOXY PHENYLACETIC ACID-mPROPYL ESTER, OF THE FORMULA OCHzC ON C 1H5 OCHa phenylacetic acid-n-propyl ester of BR 210 C.2l2 C./

0.7 mm. Hg are thus obtained.

Example 9 PREPARATION OF THE COMPOUND, 3-METHOXY-4- N,N-DIETHYLCARBAMIDOMETHOXY PHENYLACETIC ACID-n-BUTYL ESTER, OF THE FORMULA (I)CH2C ON (JHZG o o 0.11. To a solution of 5.2 grams of sodium in 2-00 milliliters (cc.) of n-butanol are added 54.4 grams of the n-butyl ester of homovanillic acid (B.P. C.-l46 C./0.5 mm. Hg) and 0.5 gram of sodium iodide. The whole is heated under a reflux condenser, and 33.8 grams of the N,N-diethylamide of chloracetic acid is added dropwise thereto. After boiling the reaction product another eight hours, it is allowed to cool, subjected to a suction filtration, and washed with n-butanol. The n-butanol is driven off in a vacuum, the residue taken up in benzene, and the benzene solution washed with a caustic soda solution and water. After drying with sodium sulfate and driving oil the solvent, the residue is distilled in a vacuum. There are thus obtained 52 grams of the n-butyl ester of 3-methoxy-4- N,N-diethylcarbamidomethoxy-phenylacetic acid, with a boiling point of 194 C./0.7 mm. Hg.

Example 10 PREPARATION OF THE COMPOUND, 3-METHOXY-4- 'N,N-DIETHYLCARBAM'IDOMETHOXY PHEN-YLACETIC ACID ALLYL ESTER OF THE FORMULA C1115 OCHa I CHzCOOO H RI OCHzC ON RI! 0 0 Ha JJHzOOOR wherein R is a member selected from. the group consisting of an alkyl of from 1 to 4 carbon atoms and an alkenyl of from 3 to 4 carbon atoms; and R and R" are joined to provide members selected from the group consisting of piperidino, pyrrolidino, and morpholino.

2. 3 methoxy 4 N,N diethylcarbamidomethoxy- 1 phenylacetic acid ethyl ester.

3. 3 methoxy 4 N tert. butylcarbamid-omethoxyphenylacetic acid ethyl ester.

4. 3 methoxy 4 pyrrol-idinocarbamidomethoxyphenylacetic acid ethyl ester.

5. 3 methoxy 4 N,N diethylcarbamidomethoxyphenylacetic acid-n-propyl ester.

6. 3 methoxy 4 N,N diethylcarbamidomethoxyphenylacetic acid methyl ester.

7. 3 methoxy 4 N,N diethylcarbamidomethoxyphenylacetic acid-n-butyl ester.

8. 3 methoxy 4 N,N diethylcarbamidomethoxyphenylacetic acid allyl ester.

No references cited. 

1. A 3 - METHOXY-4-CARBAMIDOMETHOXY - PHENYLACETIC ACID ESTER OF THE FORMULA: 